The following is a condensation of a slightly longer post which can be found at this link.
Dr. Charles Stratton's Current Thinking on How Chlamydia Pneumoniae (Cpn) Infection Causes Specific Diseases
Dr. Stratton has been observing the emerging literature and research on Cpn, as well as the clinical trials of new anti-chlamydial agents (see footnotes at bottom of this page). His unique and expert microbiological perspective on Cpn helps to shed some light on how such a singular organism can engender such multiple and varied clinical diseases.
These observations inform Dr. Stratton’s current thinking about the course and pattern of Cpn infection. I’ve attempted to diagram this below to give the reader a feel for the sequence and locus of Cpn in the body, as well as the resulting disease picture. WHile these should be termed theoretical speculations, his theoretical speculations are based on his considerable research, his expertise in microbiology, and his varied clinical experience in treating numerous Cpn infections in a variety of diseases. The picture he describes makes much clearer the multiple pathways and illnesses caused by Cpn, as well as the challenges in treating it.
Initial Infectious Entry-
The initial entry into the body for Cpn infection is through the respiratory system. Studies have demonstrated that Cpn crosses from the lungs into the blood stream via infecting macrophages, the first response immune cells which are trying to combat the respiratory infection.
These circulating infected macrophages both produce EB’s, the infectious spores of Cpn, directly into the blood stream where they attach to and are carried by red blood cells throughout the body (see the picture on our home page), and are taken up by the natural filter organs of the body where they infect those organs with Cpn.
The Inflammatory Trigger:
Stage is now set for focal diseases: any source of inflammation attracts infected macrophages and white cells as well as EB carrying red cells as part of the body’s natural repair process. Cpn then transfers from damaged macrophages via EB’s and sets up shop in inflamed areas.
At this point in the infection cycle, the type and locus of the Cpn infection then determines which disease will result and manifest symptomatically (the following is meant for example only, and is not intended to be a complete or exhaustive list):
Where specialists, and patients, tend to look at a particular disease as the problem, the microbiological perspective Dr. Stratton brings sees the problem as one of a systemically based infection.
Dr. Stratton now posits that the primary infection in Cpn is of the immune system: immune cells & bone marrow.
- It is this which, in part, causes such difficulty in getting rid of Cpn.
- It also causes continuous reinfection if the full spectrum of Cpn infection is untreated.
- It also lowers the body’s ability to cope with other bacterial and viral infections.
- This, in turn, fosters further sources of inflammation, and even has the potential (through immuno-incompetence) to compromise the body’s ability to fight cancer and other diseases.
It also answers some common questions that arise in Cpn Combined Antibiotic Protocol (CAP) treatment.
Why do viruses and cold sores “surface” during CAP treatment?
This could be due to apoptosis (cell death) of infected immune cells and resulting neutropenia which temporarily lowers your immune response until these cells are replaced. Hence latent but suppressed viruses and fungi emerge as immune cells, which previously held them in check, die.
Why is aggressive or rapid treatment of Cpn potentially dangerous?
In addition to the misery of massive endotoxin release from killing Cpn, and related cytokine (inflammatory) responses of pain and brain fog, massive kill of Cpn infected cells in the body could potentially cause crashing white counts and potential organ dysfunction or even organ failure (E.G.. liver failure) as large scale apoptosis of infected immune and organ cells occurs. As there is no quantitative measure of infectious load, and no way other than symptoms to know which organs are significantly infected, it behooves physicians treating Cpn to start gradually until some measure of the patient’s response indicates how quickly one can “ramp up” to full treatment. This also suggests that highly potent anti-chlamydial agents such as Rifabutin are not the best first-line treatment, even though they appear to be more effective at killing Cpn more quickly. Once the load has been brought down through gradual introduction of the regular CAP, then a cautious trial of such other agents can be considered.
Dr. Stratton has been paying close attention to reports of drug trials of Rifabutin, a very potent new anti-chlamydial. Even healthy young volunteers showed lowered white cells and liver problems during the Pfizer trials.
Given that Dr. Lee Stewart’s findings that 20-25% of young, healthy blood donors were found to be flow cytometry positive for Cpn, Dr. Stratton believes that these effects could be not so much side effects of Rifabutin, as it has been currently viewed, but rather a main effect of the drug, that of killing Cpn and resulting death of previously infected cells.
In other words, since Cpn infection is ubiquitous and often sub-clinical, and “side” effects from potent antichlamydial agents in so-called “healthy” volunteers are actually main effects--- the subjects were not healthy after all, just not clinically ill.
Multi-year treatment process-
Treating Cpn is a multi-year treatment process because of it’s potential to be widespread throughout in body organs, the vascular system, and immune system, as well as it’s toxicity in treatment (from endotoxins, porphyrins, inflammatory and cellular apoptosis). The more body systems involved, the longer and more difficult it is to treat, both in terms of tolerance of treatment from endotoxins, porphyria and apoptosis, as well as being able to get to all the tissues involved, which have differentials in terms of how antibiotics may concentrate in them. Cpn cells also have active pumps which try to lower concentrations of noxious substances (like antibiotics) which also have to be overcome.
How long treatment will take depends, of course, on the degree of infection, amount of bacterial load, severity of infection and number of organs involved, and so on. We don’t have any quantitative measures of infection currently. A good clinician, knowledgeable about the conditions which Cpn can cause, may be able to make an educated guess as to how many organ systems are involved on the basis of history and symptoms. Dr. Stratton sees the degree of reaction to NAC as a useful rough indicator of EB load—the more you react to it the more EB’s you have built up. He also sees the length of time one has been infected (when symptoms may have started) as a rough indicator of the length of treatment (note: one can only guess at this, as we may have initiated Cpn infection from what seemed a mild respiratory infection many years ago, and did not demonstrate serious problems such as MS until years later).
Dr. Stratton’s rule is “Go as fast as you can but no faster,” i.e. as rapidly as your own particular condition can tolerate given the above factors.
He sees that towards the latter phase of treatment, when one is no longer responding with significant reactions to metronidazole pulses, doing a course of 2 weeks on Flagyl and 2 weeks off while continuing with dual antibiotics, is a useful process to clear remaining tissues. When this is tolerated without significant side effects, a cautious trial of Zithromax and Rifabutin as a final test of Cpn clearance could be tried under careful supervision (watching for plummeting white cells and liver toxicity). At this point one should have cleared organs sufficiently that any apoptosis from the potency of Rifabutin would likely be easily tolerated.
Footnotes: Specific observations
Dr. Stratton has paid particular attention to findings by Dr. Stewart that supposedly young, healthy blood donors are showing positive cultures and flow cytometry for Cpn. Her study showed a number of very important findings with implications for our understanding of Cpn transmission and proliferation in the body.
The first is that approximately 25% of buffy coat samples (a buffy coat is the WBC— white blood cell— portion of spun blood) were culture positive for Cpn. This is not an antigen test, but means that Cpn could actually be cultured or grown in the lab from 25% of white blood cell samples. This means infectious Elementary Bodies are circulating in the blood stream.
The second significant finding in Dr. Stewart’s study, was that approximately 25% of WBC’s were seen by Flow Cytometry to have intracellular Cpn. The work of Yamaguchi, demonstrating messenger RNA from peripheral blood mononuclear cells, suggests that these intracellular Cpn found by Stewart are viable. Thus, we know that viable Cpn in WBCs and infectious Cpn elementary bodies circulate in the blood stream and can go anywhere blood goes and can infect any tissue. I will go into why Dr. Stratton sees this finding as so important in a bit.
Dr. Stratton also notes that, in her study, this 25% of donors infected with viable Cpn, both intracellular and free EB’s, occurred in so-called “young healthy blood donors.” That is, while they were culture-positive for Cpn, they have no disease symptoms and were considered to be a “normal” control sample. Dr. Stratton links this finding to reports from the Pfizer drug trials for Rifabutin, a highly potent anti-chlamydial. In the drug trials for Rifabutin there were some cases of liver failure and also of plummeting white blood cell counts in “healthy” volunteer subjects. This has been interpreted in some places as a potential side effect of the medication.
From Dr. Stratton’s perspective on the biology of Cpn, and utilizing the evidence from Stewart, Yamaguchi and others, if 25% of “healthy” volunteers are in fact infected with Cpn, including potentially liver and immune system (white cells) cells as important sites of infection (see explanation below), then a highly potent anti-chlamydial agent will kill many Cpn in parasitized cells. This could initiate large-scale apoptosis (natural cell death) of those body cells that have been inhibited from apoptosis by the Cpn which previously infected them.
Let me say that again, a little differently. We know that Cpn inhibits apoptosis of its host cell so that the host cell stays alive and the infecting Cpn survives. If you kill the Cpn invader, the host cell is no longer being prevented from it’s natural death and replacement cycle. And If you kill a bunch of Cpn all at once, you have a bunch of your body or organ cells dying all at once, and it takes time for them to be cleared by the immune system and then replaced by the natural cell replacement process. It is this, on a more gradual scale, which David Wheldon has noted makes for continuing die-off like symptoms after a Flagyl pulse has been completed.
So, if a whole bunch of liver cells undergo apoptosis at once then liver failure or liver problems could occur. Similarly, if a whole bunch of immune cells undergo apoptosis then, then macrophages and white cells die and severe neutropenia (lowered white count) could occur. From Dr. Stratton’s perspective, these reports may not be a side effect of the Rifabutin, i.e. an unintended effect of a medication, but rather could be due to it’s main effect—killing Cpn.
Prevalence of viable Chlamydia pneumoniae in peripheral blood mononuclear cells of healthy blood donors.
Yamaguchi H, Yamada M, Uruma T, Kanamori M, Goto H, Yamamoto Y, Kamiya S.
Transfusion. 2004 Jul;44(7):1072-8.
Department of Infectious Disease, Division of Microbiology, and the Department of 1st Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
BACKGROUND: Demonstration of viable Chlamydia (Chlamydophila) pneumoniae in peripheral blood mononuclear cells (PBMNCs) is essential to understand the involvement of C. pneumoniae in atherosclerosis. Nevertheless, the prevalence of viable C. pneumoniae in the blood of healthy donors has not yet been studied. STUDY DESIGN AND METHODS: The presence of C. pneumoniae transcript in PBMNCs from blood of healthy human donors was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) with primers for C. pneumoniae 16S rRNA, which is more sensitive than genomic-DNA-based analysis, and by the use of staining with fluorescein isothiocyanate-conjugated chlamydia monoclonal antibody (MoAb). RESULTS: Thirteen of 70 donors (18.5%) showed the presence of bacterial transcript in cultured PBMNCs. The prevalence of bacterial detection and bacterial numbers was significantly increased in PBMNC cultures incubated with cycloheximide. Immunostaining of PBMNCs with antichlamydial MoAb also revealed the presence of bacterial antigen in the PBMNCs judged as positive. Nevertheless, cultivation of C. pneumoniae from all PCR-positive donors was unsuccessful. There was no signifi-cant correlation between the presence of chlamydia and either sex or current smoking habits. A possible age variation, however, in the presence of chlamydia in blood of healthy donors was suggested by the results obtained. CONCLUSION: The bacterial transcripts in PBMNCs obtained from healthy donors were detected by the RT-PCR method. Viable C. pneumoniae may be present in healthy human PBMNCs.
Detection of Chlamydia in the peripheral blood cells of normal donors using in vitro culture, immunofluorescence microscopy and flow cytometry techniques
BMC Infectious Diseases 2006, 6:23 doi:10.1186/1471-2334-6-23
Frances Cirino (email@example.com)
Wilmore C. Webley
Nancy L. Croteau (Nancy.Croteau@umassmed.edu)
Chester Andrzejewski Jr. (firstname.lastname@example.org)
Elizabeth S. Stuart (email@example.com)
Eur J Haematol. 2005 Jan;74(1):77-83.
Detection of Chlamydophila pneumoniae in the bone marrow of two patients with unexplained chronic anaemia.
Central Laboratory, University Hospital Mannheim, Mannheim, Germany. firstname.lastname@example.org
Anaemia of chronic disease (ACD) is a common finding involving iron deficiency and signs of inflammation. Here, we report on two patients with ACD where a persistent infection with Chlamydophila (Chlamydia) pneumoniae (CP) was detected in bone marrow (BM) biopsies. Infection was suspected by routine cytology and confirmed by immunofluorescence, electron microscopy, polymerase chain reaction (PCR) including different primer sets and laboratories and sequencing of the PCR product. This is a first report of chlamydial presence in the BM of anaemic patients. The cases are presented because persistent chlamydial infection may contribute more frequently to chronic refractory anaemia than previously suspected.
Tolerance and Pharmacokinetic Interactions of Rifabutin
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,
0066-4804/01/$04.000 DOI: 10.1128/AAC.45.5.1572–1577.2001May 2001, p. 1572–1577 Vol. 45, No. 5
Copyright © 2001, American Society for Microbiology. All Rights Reserved.
RICHARD HAFNER,1* JAMES BETHEL,2 HAROLD C. STANDIFORD,3 STEPHEN FOLLANSBEE,4
DAVID L. COHN,5 RONALD E. POLK,6 LARRY MOLE,7 RALPH RAASCH,8 PRINCY KUMAR,9
DAVID MUSHATT,10 AND GEORGE DRUSANO11 FOR THE DATRI 001B STUDY GROUP†
This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.
Severe neutropenia among healthy volunteers
given rifabutin in clinical trials
CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2003 591
Glen Apseloff, MD
The Ohio State University
College of Medicine and Public Health
CLINICAL PHARMACOLOGY & THERAPEUTICS
Letters to the Editor DECEMBER 2003, p. 592
Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers.
J Clin Pharmacol. 1998 Sep;38(9):830-5
Department of Pharmacology, The Ohio State University College of Medicine, Columbus 43210-1239, USA.
A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.